1. Mechanisms and consequences of weight gain in Pima Indians and other human populations. Weight change involves alteration of the balance between food intake and energy expenditure. Food intake is regulated by peripheral hormones and by central satiety signals. Using data from positron emission tomography (PET) scans of the brain, we have found that the left dorsolateral prefrontal cortex, an area important in meal termination and reward processing, has lower activation after a meal compared to lean individuals. This finding is consistent in men and women. Furthermore, in individuals who have lost and kept off weight, changes activation in this area is similar to that of lean individuals, suggesting that successful weight loss is accompanied by improved activation in this area. We have also found that energy expenditure is influenced by peripheral hormones. Specifically, adiponectin, a hormone produced by fat cells, and glucagons-like peptide 1 (GLP-1), and thyroid hormones (specifically free T3) are associated with resting energy expenditure. Moreover, relatively low free T3 (still within the normal range) predicted weight gain. We have also found that a thrifty obesity phenotype, characterized by changes in energy expenditure to over and underfeeding predicts weight gain. Future plans include examination of weight loss on brain tissue density, examination of other components of the energy balance equation, in particular stool and urine energy loss, between lean and obese individuals, and examining whether obesity phenotypes defined by variation in energy expenditure in response to altered food intake can predict who weight loss in an intervention program.[unreadable] [unreadable] 2.Pathophysiology of Type 2 Diabetes (T2DM) in non-obese and obese individuals. The adipose tissue is now recognized as an organ that secretes a large number of proteins (known as adipokines). Adipokine mediated activation of the immune system may mediate the effect of adiposity on insulin action and subsequent risk of T2DM. Past work has found that macrophage inhibiting factor (MIF) may link obesity and insulin action in Pima Indians. Adipose tissue is also now known to be infiltrated by macrophages, which may mediate adipose tissue secretion of adipokines. We have found that percent body fat does correlate with macrophage count in adipose tissue. However the association with insulin action is not as strong. We are currently running a placebo controlled clinical trial designed to test if a short treatment with an anti-inflammatory drug improves insulin resistance in non-diabetic obese individuals. Past work demonstrated that fat cell size is an important predictor of development of diabetes. Our further work in this area demonstrates that fat cell size is related to excess fat accumulation in muscle and in particular in liver and may be mediated by the adipocyte hormone adiponectin. Increased liver fat accumulation is related to worsening insulin sensitivity. Insulin secretion as well as insulin action are both important risk factors for the development of T2DM. In our prospective data, we have found that in individuals with normal fasting and 2 hour plasma glucose concentrations, the acute insulin response (a measure of insulin secretion) remains an important predictor of T2DM. Prevention studies in individuals at high risk for T2DM have focused on improvement in insulin resistance, but not necessarily insulin secretion. We plan to study individuals undergoing bariatric surgery using the gastric band versus the Roux-en-Y gastric bypass technique to study how changes in nutrient flow affect insulin secretion.